Glomerulonephritis is a major cause of end stage renal disease (ESRD). While the pathogenic rote of proinflammatory cytokines, chemokines, and adhesion molecules in giomerulonephritis has been extensively studied, the renal protective role of anti-inflammatory cytokines such as TGF-beta has received little attention. In this proposed research, we will explore the role of TGF-beta in the resolution of renal inflammation and explore three novel mechanisms. First, we will examine the hypothesis that TGF-beta may signal through its inhibitory signaling protein, Smad7, to counter-regulate the activation of NF.kappaB by inhibition of IkappaBalpha degradation (phosphorylation). This is important since NF.kappaB has been shown to play a key role in glomerulonephritis. Second, we will further investigate the mechanisms of TGF-beta/Smad7 in the renal inflammation by overexpression of Smad7 in vitro and in vivo. We expect that inhibition of NF.kappaB-driven immune and inflammatory responses including expression of MHC class II, cytokines (IL-1, TNFalpha), chemokine (MCP-1), adhesion molecules (ICAM-1), iNOS, macrophage/T cell infiltration, and cell proliferation is the mechanisms by which Smad7 plays a role in anti-renal inflammation. Finally, we will determine the functional role of Smad7 in the resolution of renal inflammation and develop a novel therapeutic strategy by gene transfer of inducible Smad7 in a rat model of crescentic glomerulonephritis. These studies will therefore explore the underlying mechanisms of TGF-beta/Smad7 in negative regulation of renal fibrosis and renal inflammation. Outcomes from these studies will allow the identification of a unique negative regulating rote for Smad7 in the pathogenesis of renal fibrosis and inflammation. Importantly, inhibition of both renal inflammation and fibrosis by overexpression of Smad7 will provide new information for the development of novel therapeutic strategies to combat kidney diseases.